An optically active amino acid is widely used as a material of food products and a synthetic intermediate of medical products. For example, an L-body optically active amino acid is an important source of nutrient for animals, while a D-body optically active amino acid that is an optical isomer of the L-body optically active amino acid increases in necessity and importance as a source of medical products in recent years. Therefore, establishing a method for selectively synthesizing these L-body and D-body optically active amino acids is an industrially important issue.
As a method for eventually obtaining the optically active amino acid, there is a method for synthesizing an asymmetric alkyl compound by an asymmetric alkylation of a glycine imine ester. This synthetic method is used so often in recent years, and uses a phase-transfer catalyst (phase-transfer catalysis). In this synthetic method, two kinds of solvents which do not blend with each other are used, and the phase-transfer catalyst moves between these solutions. Thus, the asymmetric alkylation of the glycine imine ester is repeatedly carried out, and the asymmetric alkyl compound is synthesized continuously. The following will explain the synthetic method in detail by showing an example of obtaining optically pure p-(4-chlorophenyl) alanine as an end product. In this example, a cinchonine base that is one of natural alkaloids is used as the asymmetric catalyst, and the glycine imine ester and an alkyl halide are used as the sources.
In this synthetic method, water and dichloroethane are used as solvents which do not blend with each other. Here, NaOH is dissolved in the water phase, and the cinchonine base, the glycine imine ester, and the alkyl halide are dissolved in the dichloroethane phase. Next, these solvents are agitated so as to mix together. Then, in the dichloroethane phase, the cinchonine base acts as the asymmetric catalyst, and the asymmetric alkylation occurs between the glycine imine ester and the alkyl halide.
By this asymmetric alkylation, a highly optically pure asymmetric alkyl compound is produced from the glycine imine ester and the alkyl halide. Moreover, here, the cinchonine base is converted into a conjugate acid, becomes ionic, and then moves to the water phase. Then, by NaOH dissolved in the water phase, the ionic cinchonine is again converted into a neutral cinchonine base, and returns to the dichloroethane phase. The cinchonine base in the dichloroethane phase catalyzes the asymmetric alkylation.
By repeatedly carrying out a series of alkylation steps, an asymmetric alkyl compound synthesizing method of the conventional technology can synthesize the highly optically pure asymmetric alkyl compound in high yield. Here, the produced asymmetric alkyl compound contains an (R)-body optical isomer(s) and an (S)-body optical isomer(s). In the produced asymmetric alkyl compound, the (R)-body optical isomer is larger in amount than the (S)-body optical isomer or the (S)-body optical isomer is larger in amount than the (R)-body optical isomer. Therefore, the optically pure asymmetric alkyl compound can be separated by recrystallization from the asymmetric alkyl compound. Thus, the optically pure asymmetric alkyl compound can be obtained. Further, the optically pure asymmetric alkyl compound thus obtained is, for example, hydrolyzed so that any amino acid can be synthesized.
The asymmetric alkyl compound synthesizing method as above is disclosed in, for example, O'Donnell, M. J.; Wu, S.; Hoffman, C. Tetrahedron, Vol 50, 4507-4518, 1994 (hereinafter referred to as “Conventional Example 1”) and Lygo, B.; Wainwright, P. G. Tetrahedron Lett., Vol 38, 8595-8598, 1997 (hereinafter referred to as “Conventional Example 2”).
However, the conventional technologies disclosed in Conventional Examples 1 and 2 cannot synthesize the asymmetric alkyl compound in a short time efficiently.
For example, in the conventional methods, the asymmetric alkylation is carried out at an interphase (interface) between the dichloroethane phase and the water phase. Therefore, it is necessary to increase the area of the interface as much as possible so that the asymmetric alkylation is efficiently carried out. To increase the area of the interface as much as possible, the solvents of water and dichloroethane needs to be agitated continuously and vigorously. As a result, the asymmetric alkylation is carried out unstably because of the unevenness of the agitation. Moreover, to obtain a product in high yield, long agitation (longer than 20 hours) is necessary. Further, when extracting the product obtained by the asymmetric alkylation, it is necessary to use a large amount of solvent different from the solvent used for the asymmetric alkylation. Therefore, an operation of extracting the product is troublesome.